It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (for example, see Life Science, Vol. 17, 1975, p. 503). Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine nerve fibers project in an extremely broad range in the brain, which supports various pharmacological effects of histamine (for example, see Journal of Comprehensive Neurology, Vol. 273, p. 283).
The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking action, sexual action, etc.) (for example, see Progress in Neurobiology, Vol. 63, p. 637 (2001)).
The existence of projection to the brain region that relates to vigilance sustenance, for example, to cerebral cortex suggests the role in control of vigilance or vigilance-sleep cycle. The existence of projection to many peripheral structures such as hippocampus and amygdaloid complex suggests the role in control of autonomic nerves, emotion, control of motivated action and learning/memory process.
When released from producing cells, histamine acts with a specific polymer that is referred to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for control of various body functions. Heretofore, four types of histamine receptors have been found. In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, histamine-H3 receptor, has been shown by various pharmacological and physiological studies (for example, see Trends in Pharmacological Science, Vol. 8, p. 24 (1986)); and recently, human and rodent histamine-H3 receptor genes have been identified and their existence has been made clear (for example, see Molecular Pharmacology, Vol. 55, p. 1101 (1999)).
It is suggested that histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the release of histamine and controlling the release of other neurotransmitters. Specifically, it is reported that a histamine-H3 receptor agonist, or its antagonist or inverse-agonist controls the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve ending. For example, the release of these neurotransmitters is inhibited by an agonist such as (R)-(α)-methylhistamine inhibits, and is promoted by an antagonist or inverse-agonist such as thioperamide (for example, see Trends in Pharmacological Science, Vol. 19, p. 177 (1998)).
Recent studies have shown that histamine-H3 receptor has extremely high homeostatic activities (endogenous agonistic factor, e.g., activity observed in the absence of histamine) in the receptor-expressing cells/tissues or in a membrane fraction derived from the expressing cells/tissues and even in living bodies (for example, see Nature, Vol. 408, p. 860). It is reported that these homeostatic activities are inhibited by an inverse-agonist. For example, a homeostatic self-receptor activity is inhibited by thioperamide or syproxyfan, and, as a result, the release of neurotransmitters from nerve ending, for example, the release and liberation of histamine from it is thereby promoted.
In animal experiments with rats, a high-level selective inhibitor of histamine synthase (histidine decarboxylase) inhibits the vigilance of rats, which suggests that histamine may function for controlling motive vigilance, Administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to cats increases their deep slow-wave sleep (for example, see Brain Research, Vol. 523, p. 325 (1990)). Contrary to this, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently increase vigilance. In addition, thioperamide decreases slow-wave and REM sleep (for example, see Life Science, Vol. 48, p. 2397 (1991)).
A histamine-H3 receptor antagonist or inverse-agonist, thioperamide or GT-2331 decreases the emotional cataplexy and sleep of narcoleptic dogs (for example, see Sleep, Vol. 24, Summaries, A, p. 23 (2001)). These pieces of information suggest that the H3 receptor may participate in vigilance-sleep control and in diseases accompanied by sleep deficiency, further suggesting a possibility that a selective H3-agonist or its antagonist or inverse-agonist may be useful for remedy of sleep disorders and other various diseases accompanied by sleep disorders (for example, idiopathic hypersomnnia, repetitive hypersomnnia, true hypersomnnia, narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, night worker sleep insanitation, idiopathic insomnia, repetitive insomnia, true insomnia, melancholia, shinzophrenia).
In animal experiments with rats, administration of a histamine-H3 receptor antagonist or inverse-agonist, thioperamide or GT-2331 to rats improved learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) (for example, see Behavioral Brain Research, Vol. 131, p. 151 (2002)). These pieces of information suggest a possibility that that a selective H3-agonist or its antagonist or inverse-agonist may be useful for remedy and/or prevention of learning disorder or attention deficit hyperactivity disorder.
In animal experiments with rats, administration of histamine to the ventricle of rats inhibited their eating action, therefore suggesting that histamine may participate in control of eating action (for example, see Brain Research, Vol. 793, p. 279 (1998)).
A histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently inhibits eating action. In addition, thioperamide promotes intracerebral histamine release (for example, see Life Science, Vol. 69, p. 469 (2001)). These pieces of information suggest that the H3 receptor may participate in eating action control, further suggesting a possibility that an H3 antagonist or inverse-agonist may be useful for prevention or remedy of metabolic diseases such as eating disorder, obesity, diabetes, emaciation, hyperlipemia.
In animal experiments with rats, administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to rats dose-dependently lowered their basal diastolic pressure. Its action was antagonized by a histamine-H3 receptor antagonist or inverse-agonist, thioperamide (for example, see Journal of Physiology and Pharmacology, Vol. 49, p. 191 (1998)). These pieces of information suggest that a histamine-H3 receptor may participate in control of blood pressure, heart beat and cardiac output, further suggesting a possibility that a histamine-H3 receptor agonist or its antagonist or inverse-agonist may be useful for prevention or remedy of circulatory system diseases such as hypertension and various cardiac disorders.
In animal experiments with rats, administration of a histamine-H3 receptor agonist, (R)-(α)-methylhistamine to rats lowered their object recognition and learning effects in the object recognition test and the passive turnout test with them. On the other hand, in the scopolamine-induced amnesia test with them, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently relieved their amnesia induced by the chemical (for example, see Behavioural Brain Research, Vol. 104, p. 147 (1999). These pieces of information suggest a possibility that a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of various diseases accompanied by memory and learning disorder, for example, Alzheimer's disease, Parkinson's disease or attention deficit/hyperactivity disorder.
It is shown that, in animal experiments with rats, a histamine-H3 receptor antagonist or inverse-agonist, thioperamide dose-dependently inhibited the spasm induced by electric shock or the epileptoid seizure induced by pentylene tetrazole (PTZ) (for example, see European Journal of Pharmacology, Vol. 234, p. 129 (1993) and Pharmacology Biochemistry and Behavior, Vol. 68, p. 735 (2001)). These pieces of information suggests a possibility that a histamine-H3 receptor antagonist or inverse-agonist may be useful for prevention or remedy of epilepsy or central spasm.
In addition to the above-mentioned thioperamide or cycloxyfan, for example, a compound of the following formula (A):
is described as a histamine-H3 receptor-antagonistic or inverse-agonistic compound (WO02/40461).
The compound of formula (A) has a propylene group between the pyrrolidinyl group and the oxygen atom therein, and it differs from compounds (I) of the present invention in that the oxygen atom directly bonds to the pyrrolidinyl group in the latter. Further, they differ in that, in the compound of formula (A), a phenyl group bonds to the oxygen atom, but in the compounds of the present invention, a group of the following formula (I-1)
wherein the symbols have the same meanings as above, bonds to the oxygen atom, and at least one of X1, X2 and X3 in the ring is a nitrogen atom.
A compound of the following formula (B):
is described as a histamine-H3 receptor antagonistic compound (for example, WO02/06223).
The compound of formula (B) has a 4-acetyl-phenoxy group and a pyrrolidinyl group that are a part of the constitutive elements of the compounds of the present invention, but its structure differs from that of the compounds of the present invention in that a propylene group exists between the 4-acetyl-phenoxy group and the pyrrolidinyl group in the former. In addition, the position of the nitrogen atom in the pyrrolidinyl group in formula (B) differs from that in the compounds of the present invention.
A compound of the following formula (C):
is described as a histamine-H3 receptor antagonistic compound (for example, JP-A 2003-064081).
The compound of formula (C) has an octandyropyrido[1,2-a]pyrazinyl group, but this differs from the compounds of the present invention in that the moiety Y in a formula (I) representing the latter is a monocyclic or bicyclic group having one nitrogen atom in the ring, such as a pyrrolidinyl group or an octahydroquinolidinyl group. In addition, they essentially differ in the point of their structures in that, in formula (C), the octandyropyrido[1,2-a]pyrazinyl group bonds to the oxygen atom via a propylene group therebetween, but in the compounds of the present invention, the corresponding groups bond directly to each other with no alkylene group therebetween.
A compound having an N-isopropyl-piperidin-4-yl group of the following formula (D):
is described as a compound that strongly and selectively bind to a histamine-H3 receptor (for example, see WO03/024929). The compound of formula (D) corresponds to the compounds of the present invention in that it has an N-isopropylpiperidin-4-yl group, but they differ in the following points: The compounds of formula (I) of the present invention do not have a biphenyl group; and in the compound of formula (D), the biphenyl group bonds to the N-isopropylpiperidin-4-yl group via a carbamoylmethyl group therebetween, but in the compounds of formula (I) of the present invention, the substituted piperidinyl group bonds to a group of formula (I-1):
wherein the symbols have the same meanings as above, via an oxygen atom therebetween.
A compound having an N-benzylhomopiperidin-3-yloxy group of the following formula (E):
is described (for example, WO01/19817).
The compound of formula (E) differs from the compounds of the present invention in the point of the position of N of homopiperidine. Further, the compound of formula (E) has the property of a nicotinic acetylcholine receptor ligand, but the compounds of the present invention have the property of a histamine-H3 receptor antagonist or inverse-agonist. In addition, WO01/19817 does neither have a description to say that the compound of formula (E) may act as a histamine-H3 receptor antagonist or inverse-agonist, nor have a description to suggest it.
A compound having an N-ethylpyrrolidin-3-yloxypyrazinyl group of the following formula (F):
is described (for example, WO01/60806). The structure of the compound of formula (F) differs from that of the compounds of the present invention in that the former has a methyl group at the 3- and 6-positions of the pyrazine ring in formula (F). Regarding its use, the compound of formula (F) is a CRF receptor ligand, and WO01/60806 does neither have a description to say that the compound may act as a histamine-H3 receptor antagonist or inverse-agonist, nor have a description to suggest it.
The present invention is to provide a heteroaryloxy-nitrogen-containing saturated heterocyclic derivative that has an action of antagonizing histamine to bond to a histamine-H3 receptor, or has an activity of inhibiting the homeostatic activity of a histamine-H3 receptor, and to provide a preventive or a remedy comprising it for metabolic system diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver; circulatory system diseases, for example, stenocardia, acute/congestive cardiac insufficiency, cardiac infarction, coronary arteriosclerosis, hypertension, nephropathy, sleep disorder and various diseases accompanied by sleep disorder such as idiopathic hypersomnnia, repetitive hypersomnnia, true hypersomnnia, narcolepsy, sleep periodic acromotion disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, night worker sleep insanitation, idiopathic insomnia, repetitive insomnia, true insomnia, electrolyte metabolism disorder; and central and peripheral nervous system diseases such as bulimia, emotional disorder, melancholia, anxiety, epilepsy, delirium, dementia, shinzophrenia, attention deficit/hyperactivity disorder, memory disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, recognition disorder, motion disorder, paresthesia, dysosmia, epilepsy, morphine resistance, narcotic dependency, alcoholic dependency.